Despite significant improvements in the early detection of malignant gliomas, the median survival of patients remains less than 12 months from the time of diagnosis (Benedetti et al., “Gene Therapy of Experimental Brain Tumors Using Neural Progenitor Cells,” Nature Med., 6:447–450 (2000); Russell et al., Pathology of Tumors of the Nervous System, (Arnold, Ed.), London (1989)). Malignant gliomas rarely metastasize outside the central nervous system, but they will diffusely invade the host brain. Peritumor brain tissue shows various types of inflammatory responses, including activated macrophages and microglia, hypertrophic reactive astrocytes, vascular invasion and edema formation (Schiffer, D., “Brain Tumors. Biology, Pathology, and Clinical References” Springer, New York, Berlin, Heidelberg (1997)). Neurons are preserved in the immediate vicinity of some tumors, but other tumors are surrounded by degenerating neurons, progressing to neuronal loss (Id). Variability in the local presentation of resident neurons has been a frequent but unexplained observation in tumor neuropathology. A similar variable observation has been the incidence of epileptic activity in glioblastoma, which approaches 50% of all cases (Cascino, G., “Epilepsy and Brain Tumors: Implications for Treatment,” Epilepsia, 31:S37–44 (1990); Pallias, J. E., “A Review of 2,413 Tumours Operated Over a 30-year Period,” J. Neuroadiol., 18:79–106 (1991)).
Human glioma cells actively release the excitatory amino acid. glutamate in vitro, and the extracellular levels of glutamate are increased both in and around experimental glioma implants in vivo (Pallias, J. E., “A Review of 2,413 Tumours Operated Over a 30-year Period,” J. Neuroadiol., 18:79–106 (1991); Ye et al., “Compromised Glutamate Transport in Human Glioma Cells: Reduction-Mislocalization of Sodium-Dependent Glutamate Transporters and Enhanced Activity of Cystine-Glutamate Exchange,” J. Neurosci., 19:10767–10777 (1999); Behrens et al., “Extracellular Glutamate and Other Metabolites in and Around RG2 Rat Glioma: An Intracerebral Microdialysis Study,” J. Neurooncol., 47:11–22 (2000)). Glutamate is the principal excitatory transmitter within the vertebrate nervous system. Approximately 40% of all synaptic terminals release glutamate, and glutamate mediates many physiological functions by activation of different receptor types (Watkins and Evans, “Excitatory Amino Acid Transmitters,” Annu. Rev. Pharmacol., 21:165–189). Two main categories of glutamate receptors have been identified, including ionotropic glutamate receptors and metabotropic glutamate receptors. Ionotropic glutamate receptors can be subdivided into N-methyl-D-aspartate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA), and kainate receptors.
There is considerable experimental and clinical evidence indicating that glutamate is involved in the pathogenesis of neuronal degeneration in the context of hypoxia/ischemia and trauma of the central nervous system, seizures and hypoglycemia. In addition, glutamate is thought to be involved in the pathogenesis of chronic neurodegenerative disorders, such as amyotrophic lateral sclerosis, Huntington's Disease, Alzheimer's Disease, and Parkinson's Disease. Functional glutamate receptors have been identified in lung, muscle, pancreas, and bone (Mason et al., Bone 20:199–205 (199); Patton et al., Bone 22:645–649 (1998)). Glutamate receptors have also been demonstrated to be involved in the suppression of neuroblastoma cells (European patent application EP1002535A1). However, no link has been established so far between glutamate receptors and glial cell tumors. While recent data show that cultured glioma cells secrete glutamate, the growth potential of glial cell brain tumors has not yet been linked to an excitotoxic mechanism.
Glial tumors, the most prevalent and morbid of which is astrcoytoma and its aggressive derivative glioblastoma multiforme, are the most common cancers of the adult central nervous system. They are also among the least treatable cancers, with a 5 year survival after initial diagnosis of <10% for tumors initially diagnosed at the grade 3 (anaplastic astrocytoma) or 4 (glioblastoma) stages. The currents treatment of glioma and glioblastoma are lacking, and achieve only palliation and short-term increments in survival. They include surgical resection—following which ultimate recurrence rates are over 90%—as well as radiation therapy, and chemotherapies that include cis-platin, BCNU and other mitotic inhibitors. The benefits of these current therapies are brief and temporary, and none are curative (e.g., Schiffer, D. Brain Tumors. Biology, Pathology, and Clinical References Springer-Verlag (New York, Berlin, Heidelberg, 1997).
The present invention overcomes the deficiencies in the relevant art.